Nano-structured microspheres and/or micro-composites formed by active ingredients and biopolymer are the most promising pharmaceutical formulations for the production of controlled release systems. They are conventionally produced using various techniques, such as grinding, spray-drying, solvent evaporation from emulsions, hot-melt extrusion, etc.; however, in many cases the production of microspheres with a controlled particle size and distribution in the micro- and nano-range still remains a challenge.
The most common technology for the production of microspheres consists of grinding a solid dispersion of drug and polymer; such process is, for example, disclosed in the patent publication WO 98/15263 (Takechi et al., Takeda Chemical Industries Ltd.). In this case, the proposed technology is to solubilize the polymer and the drug in the same solvent. Subsequently, the solvent is evaporated under vacuum, producing a solid dispersion of the active substance in the polymer, that is then milled.
Alternatively, micro and nano-composites can be obtained by spray-drying of a water-in-oil emulsion, where the drug is solubilized in the aqueous phase and a polymer is solubilized in the oily phase. An example of the above-described technique is reported in EP 0145240 (Okada et al., Takeda Chemical Industries Ltd.), and in the corresponding patents the U.S. Pat. No. 4,652,441, U.S. Pat. No. 4,711,782, U.S. Pat. No. 4,917,893. More specific processes of solvent evaporation from emulsions are described in EP 0481732 (Yamada et al., Takeda Chemical Industries Ltd.). In this case, the first step of the process requires the production of primary water-in-oil emulsion (W/O) that is, subsequently, added to a second water phase in order to form a double emulsion of water-oil-water (W/O/W). The solvent removal by evaporation under vacuum allows the production of micro-composite structures. High residual solvent values and large polydispersion of the final products are unresolved issues of the technologies described above.
To date, several technologies have been proposed for the production of micro- and nano-particles and/or micro-spheres that use compressed and/or supercritical carbon dioxide. A brief description of these processes is reported below.
The rapid expansion of solutions obtained by compressed and/or supercritical carbon dioxide is the first technology that showed an industrial interest, with a first patent application in 1985, filed by the Battelle Memorial Institute with the number WO 85/00993 (R. D. Smith). This process involves the formation of a solution with the compound to be micronized in a compressed gas and its subsequent precipitation in a lower pressure collection chamber. This technology is also proposed for the production of micro-structured materials in the patent publications by the University of Delaware, WO 98/15348 (Shine et al.); Mainelab e Laboratorires des Produits Ethiques Ethypharm, WO 01/89481 (Dulieu et al.); Centre de Microencapsulation, U.S. Pat. No. 6,087,003 (Benoit et al.); BASF Aktiengesellschaft, EP-A-1016454 and U.S. Ser. No. 60/375,873 (Lockemann et al.); US 2002/130430 (Trevor P. Castor).
Supercritical carbon dioxide has also been proposed as anti-solvent to induce the fast precipitation of a solute from a liquid solution in the form of micro- and nano-particles. This technology appeared for the first time in a patent application by The Upjohn Company, in 1988 (U.S. patent application Ser. No. 253,849; W. J. Schmitt), subsequently filed as WO90/03782 and corresponding to U.S. Pat. No. 5,707,634. The said patent claims the production of micro-particles made of a wide range of materials, including polymeric substances. Subsequently, the concerned technique has been proposed for the formation of nano-materials and micro-structured polymers, for example in the patent documents owned by: Schwarz Pharma, U.S. Pat. No. 5,043,280 (Fischer et al); Fidia Advanced Biopolymers, WO 96/29998, U.S. Pat. No. 6,214,384 and U.S. Pat. No. 6,541,035 (inventors Pallado et al.); Mainelab, WO 01/12160 (Richard et al.).
The use of supercritical carbon dioxide has also been described for the treatment of emulsions with a discontinuous process by Astra Aktiebolag, WO 99/52507 (Andersson et al.) and by Separex, WO 02/092213 (Perrut et al.). In these patent publications, the main steps are as follows: preparation of an aqueous solution containing the active ingredient and preparation of an emulsion or micro-emulsion W/O of the aqueous solution in an organic solvent, in which the coating polymer was previously solubilized or, alternatively, preparation of a emulsion in which the active substance and the carrier are solubilized in only one of the two phases. Such emulsions are then sprayed in supercritical carbon dioxide, which extracts one or both phases, producing drug-polymer micro-spheres. The two proposed processes are substantially an application of the anti-solvent technology; therefore, they are discontinuous and require the collection of micro-spheres on a filter at the bottom of the precipitator vessel.
The Ferro Corporation has also filed a patent application published as US 2006/0153921 (Chattopadhyay et al.) which describes a process using supercritical carbon dioxide for the production of micro-spheres. The proposed process is performed by injecting an O/W emulsion in supercritical carbon dioxide through an injector; the supercritical fluid extracts the organic solvent, thus producing micro-particles that are recovered in a suspension in the bottom of the high-pressure vessel. The microspheres are finally recovered by freeze-drying. The proposed process has a batch layout and is very similar to the supercritical anti-solvent technology, already described in the several previously cited patent documents. Indeed, in this process the contact between the O/W emulsion and the supercritical solvent is made at the exit of the injector, where the formation of emulsion drops is obtained. As a consequence, the contact time between the two fluids could be not enough for the complete solvent extraction; i.e., the emulsion droplet time of flight, before falling into the liquid, is very short and may produce an incomplete extraction of the oily phase.
Other processes for producing micro- and nano-particles using mixtures and/or gas saturated solutions are described in the following patent publications: Ferro Corporation, WO 02/20624 (Mandel et al.); University of Colorado, U.S. Pat. No. 6,095,134 (Sievers et al.); University Technology Corporation, WO 00/75281 (Sievers et al.); Micro & Nano Materials, WO 03/004142 (Reverchon E.); Separex, WO 01/49407 (Perrut M.,) and WO 02/32462 (Perrut M. et al.).
Even if the literature documents described above use compressed and/or supercritical CO2 for the production of micro- and nano-particles and/or micro-spheres, none of them discloses expanded liquid used in the emulsion or micro-emulsion formulation. Moreover, none of the mentioned documents is related to an “expanded emulsion” extraction in a continuous packed column by using an “expanded liquid” in order to produce nano- and/or micro-particles and/or microspheres. Finally, all the said processes can operate only in batch or, at least, in semi-continuous mode, i.e., although the processing fluids may be continuously supplied, the micronized particles recovery always requires the depressurization of the precipitator vessel.
It is also worth of note that the process proposed according to the present invention is completely different from the conventional liquid-liquid extraction or alternative liquid-compressed gas extraction as described in the following documents: Norsk Hydro, WO 98/32819 (M. Perrut); Fried. Krupp GmbH, U.S. Pat. No. 5,229,000 (Ben-Nasr H. et al.); M & G Ricerche, WO 93/03064 (Al Ghatta et al.). In these documents, and in similar ones, supercritical carbon dioxide is used exclusively for the fractionation of liquid mixtures. A continuous formation of nano- and micro-particles and/or micro-spheres in solid suspensions in a packed column it is not reported.